Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models.
<h4>Objective</h4>Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this st...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0321598 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850128325332172800 |
|---|---|
| author | Guoqiao Wang Zhaolong Adrian Li Ling Chen Heather Lugar Tamara Hershey |
| author_facet | Guoqiao Wang Zhaolong Adrian Li Ling Chen Heather Lugar Tamara Hershey |
| author_sort | Guoqiao Wang |
| collection | DOAJ |
| description | <h4>Objective</h4>Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome.<h4>Methods</h4>We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model.<h4>Results</h4>Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group.<h4>Conclusions</h4>For rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs. |
| format | Article |
| id | doaj-art-4c21156aa0ec409ab89cbee0f8337c27 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-4c21156aa0ec409ab89cbee0f8337c272025-08-20T02:33:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01205e032159810.1371/journal.pone.0321598Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models.Guoqiao WangZhaolong Adrian LiLing ChenHeather LugarTamara Hershey<h4>Objective</h4>Wolfram syndrome, an ultra-rare condition, currently lacks effective treatment options. The rarity of this disease presents significant challenges in conducting clinical trials, particularly in achieving sufficient statistical power (e.g., 80%). The objective of this study is to propose a novel clinical trial design based on real-world data to reduce the sample size required for conducting clinical trials for Wolfram syndrome.<h4>Methods</h4>We propose a novel clinical trial design with three key features aimed at reducing sample size and improve efficiency: (i) Pooling historical/external controls from a longitudinal observational study conducted by the Washington University Wolfram Research Clinic. (ii) Utilizing run-in data to estimate model parameters. (iii) Simultaneously tracking treatment effects in two endpoints using a multivariate proportional linear mixed effects model.<h4>Results</h4>Comprehensive simulations were conducted based on real-world data obtained through the Wolfram syndrome longitudinal observational study. Our simulations demonstrate that this proposed design can substantially reduce sample size requirements. Specifically, with a bivariate endpoint and the inclusion of run-in data, a sample size of approximately 30 per group can achieve over 80% power, assuming the placebo progression rate remains consistent during both the run-in and randomized periods. In cases where the placebo progression rate varies, the sample size increases to approximately 50 per group.<h4>Conclusions</h4>For rare diseases like Wolfram syndrome, leveraging existing resources such as historical/external controls and run-in data, along with evaluating comprehensive treatment effects using bivariate/multivariate endpoints, can significantly expedite the development of new drugs.https://doi.org/10.1371/journal.pone.0321598 |
| spellingShingle | Guoqiao Wang Zhaolong Adrian Li Ling Chen Heather Lugar Tamara Hershey Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models. PLoS ONE |
| title | Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models. |
| title_full | Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models. |
| title_fullStr | Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models. |
| title_full_unstemmed | Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models. |
| title_short | Clinical trials for Wolfram syndrome neurodegeneration: Novel design, endpoints, and analysis models. |
| title_sort | clinical trials for wolfram syndrome neurodegeneration novel design endpoints and analysis models |
| url | https://doi.org/10.1371/journal.pone.0321598 |
| work_keys_str_mv | AT guoqiaowang clinicaltrialsforwolframsyndromeneurodegenerationnoveldesignendpointsandanalysismodels AT zhaolongadrianli clinicaltrialsforwolframsyndromeneurodegenerationnoveldesignendpointsandanalysismodels AT lingchen clinicaltrialsforwolframsyndromeneurodegenerationnoveldesignendpointsandanalysismodels AT heatherlugar clinicaltrialsforwolframsyndromeneurodegenerationnoveldesignendpointsandanalysismodels AT tamarahershey clinicaltrialsforwolframsyndromeneurodegenerationnoveldesignendpointsandanalysismodels |